PROJECT SUMMARY Ovarian cancer (OC) patients experience significant psychological distress, which often persists after treatment and causes poor quality of life (QOL). Chronic stress/distress may promote cancer growth through prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, which alters expression of various cytokines such as IL-6 and VEGF, leading to increased angiogenesis, invasion, and metastasis. Excess cortisol, a result of chronic HPA axis activation, may also have direct effects on tumor growth. These biomarkers predict poor prognosis in OC patients. Exercise is associated with reduced distress and improved QOL in OC survivors. Observational studies suggest that exercise may decrease recurrence and improve survival in cancer patients, but few clinical trials have evaluated the effects of exercise specifically in OC survivors, and none have evaluated the effects of exercise on biomarkers of angiogenesis, or its effects on chronic stress/distress. In our proposed 2-arm randomized controlled trial (RCT), we will test the effects of a six-month moderate-intensity home-based exercise intervention in OC survivors who have recently completed primary treatment versus controls on (1) nocturnal cortisol and urinary norepinephrine levels, markers of chronic stress; (2) biomarkers of angiogenesis (IL-6, VEGF); (3) levels of distress and QOL, assessed by patient-reported outcomes. Women with stage II-IV OC (N=98 randomized) who have completed adjuvant chemotherapy within one to six months and are in clinical remission will be randomized to a 24-week home-based exercise program or wait-list control. The exercise prescription will consist of 150 minutes of moderate aerobic exercise per week. The intervention will be delivered by a behaviorally-trained exercise physiologist and will include one in-person exercise teaching session (with goals set based on the participant's exercise and health status), followed by weekly telephone- based support. The control group will maintain habitual levels of physical activity, and will be offered the exercise intervention after completion of the 24-week study. Baseline and 24-week assessments will include serum levels of IL-6 and VEGF, salivary cortisol levels measured at bedtime for 3 consecutive days, 24 hour urinary norepinephrine levels, and validated questionnaires assessing levels of distress and health-related QOL. Compliance to the exercise intervention will be assessed by daily activity logs, completion of weekly telephone calls with the exercise physiologist, and actigraphs. IMPACT: The majority of women with OC experience poor QOL and ultimately die of their disease despite conventional therapy. Determining if exercise can improve QOL and biomarkers of prognosis would be a major advance for women with OC. The data from this R21 will justify a larger RCT of moderate exercise in OC survivors that will be powered to detect a difference in progression-free survival and further elucidate the biobehavioral pathways through which physical activity may affect OC prognosis and survival.